Activating Pyruvate Dehydrogenase Complex to Improve Barth Syndrome Cardiac Function

Charles E. McCall, PhD, Professor, Wake Forest University Health Sciences

Heart failure is the dominant, life-threatening complication of BTHS, a disease caused by mutations in the tafazzin (TAZ) gene. TAZ mutations cause dysregulation of a vital molecule in the mitochondria of cardiac cells, called cardiolipin, that is necessary for normal energy production by the heart’s mitochondria, the “power houses” of cells. Our BTHS Foundation Development Grant uses a novel therapeutic strategy designed to reverse TAZ-associated cardiolipin repression of mitochondrial energetics in the heart. To test this potential new treatment, we will employ a heart-specific genetic mouse model of BTHS to compare how cardiolipin normally supports cardiac energy metabolism, but is deregulated in BTHS. Based on our recent discovery that BTHS cardiolipin disrupts glucose conversion to energy at a specific enzymatic site in mitochondria, we will determine whether the investigational drug dichloroacetate (DCA) improves the energy defect in the hearts of mutant mice. DCA is already being tested in an FDA and NIH-supported phase 3 clinical trial in children with another primary mitochondrial disease that affects the same enzyme disrupted in BTHS. Thus, this development project's scientific and potential clinical impact seeks to advance our understanding and treatment of a previously unknown mechanism underlying BTHS cardiac failure. Our success could lead to a clinical trial of DCA in treating children with BTHS syndrome and may also encourage future research into the causes and treatment of other complications of BTHS involving skeletal muscle function and growth.

This project’s funding was made possible by the generous support of the Will McCurdy Fund for Advancement in Therapies for Barth Syndrome.